BACKGROUND: Conditioned pain modulation (CPM) methods are experimental procedures to assess presumed descending nociceptive modulatory pathways. Various CPM-methods are currently used, making the comparison of results difficult. The aim of this study was to compare five conditioning stimuli and to evaluate the influencing effects of personal factors on CPM-efficacy. METHODS: 101 healthy pain-free adults (50 males, 51 females) participated in this cross-sectional study with repeated measures design. The CPM-method consisted of hot water immersion (46°C, HWI), cold pressor test (12°C, CPT), cold pack application, and single and double ischemic occlusion as conditioning stimuli in randomized order. Pressure pain threshold was used as test stimulus at the mm. trapezius and quadriceps for all CPM-protocols. RESULTS: All CPM-protocols resulted in effective CPM, although cold pack application revealed smaller CPM-magnitudes compared to all other methods at both muscles, except single ischemic occlusion at the m. quadriceps. A smaller CPM-effect at the m. trapezius was shown when CPM was provoked by single ischemic occlusion compared to the CPT. Chronic stress, gender, attentional focus, age, physical activity and perceived pain are all influencing factors, in various conditioning stimuli at the mm. trapezius and quadriceps. CONCLUSIONS: CPT and HWI seem to be the most appropriate conditioned pain modulation paradigms for research settings, while single and double ischemic occlusion seem to be more useful for clinical settings. Influencing factors to be considered are gender, age, stress, physical activity, perceived pain and attentional focus to the conditioning stimulus, but depend on the test site and exerted method. SIGNIFICANCE: Hot water immersion, cold pressor test, and single and double ischemic occlusion result in comparable CPM-effects at the mm. trapezius and quadriceps. Anti-nociceptive effects of the cold pack are mainly a result of attention towards the cold pack. Chronic stress, attentional focus towards the conditioning stimulus and perceived pain of the conditioning stimulus influenced the anti-nociceptive effects at the m. trapezius. Gender and level of physical activity influenced the anti-nociceptive effects with the other methods at the m. quadriceps.